A central issue in biogerontology is the nature of the mechanisms that modulate species lifespan. Genetic studies in Caenohabditis elegans and Drosophila melanogaster have identified a cellular pathway that modulates longevity. Mutations that reduce the function of the homolog of the IGF-I/insulin receptors extends lifespan in both nematodes and flies. Similarly, studies in rodents indicate that a reduction in the growth hormone/IGF-I axis leads to an extension in lifespan. These studies suggest that a reduction in IGF-I may extend lifespan in mammals but no direct evidence for this hypothesis exists. We propose to test directly the possibility that a reduction in IGF-I levels can increase lifespan using a transgenic mouse model. We have obtained a unique transgenic mouse line that contains an insertion in the igf-1 gene leading to a specific reduction in IGF-I and a dwarf phenotype (IGF-I m/m mice). Specific aim 1 will examine survival of the IGF-I mice relative to controls over the course of this study and Specific aim 2 will examine age related changes in the IGF-I m/m mice such as immune senescence, collagen crosslinking and hormonal changes to determine whether there is any change relative to controls. Our long-term goals are to perform complementation analysis using the IGF-I m/m mice and mice that harbor other mutations that are known to extend lifespan. In this way, we can determine whether these mutations act through separate or common mechanisms to regulate longevity. In parallel to the mouse studies we plan to identify the IGF-I dependent pathways relevant to longevity using cell culture models derived from these mice.